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The Design and Synthesis of Duocarmycin Prodrugs

Kerr, Natalia Ortúzar; (2006) The Design and Synthesis of Duocarmycin Prodrugs. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The design of targeted prodrugs has become a viable aim in cancer chemotherapy, as research moves away from classical cytotoxic agents. The development of various compounds that exploit tumour physiological and protein expression profiles for targeted activation is reviewed. Cytochrome P450 enzymes, either overexpressed intratumourally or introduced by gene therapy, have potential for activation of deshydroxy prodrug analogues of the duocarmycins via bioxidation of the pharmacophore. The duocarmycins are potent antitumour antibiotics capable of sequence-selective alkylation of DNA. They bind in the minor groove and exhibit high selectivity towards AT rich sequences. Herein, the synthesis of deshydroxy-seco-CI-MI 59 and the fluorinated derivative 105 by two complementary routes is described. These prodrugs are based on the minimum potent pharmacophore of the duocarmycins (CI). Initial investigations of the 5-exo-trig free radical cyclisation with catalytic Bu3SnH, using polymethylhydrosiloxane (PMHS) as a hydride source gave good yields. This was further improved by the use of tris(trimethylsilyl)silane (TTMSS) in stoichiometric quantities. An alternative route involving alkylation of a 2-fluoronitrobenzene with dimethyl malonate was also developed. Functional group interconversions allowed a 5-exo-tet nucleophilic substitution to form the A ring. This synthesis allows the application of an enzyme- based resolution of an early intermediate without downstream racemisation. Deprotection and coupling to 5-methoxyindole-2-carboxylic acid 60 gave an extended prodrug in good yield. Duocarmycin SA 19 is among the most potent compounds in this class of natural products. Synthesis of the deshydroxy-seco-DSA pharmacophore was also achieved using the 5-exo-trig free radical cyclisation. A methoxy prodrug 126, where the activity is removed by ether formation rather than removal of the hydroxyl group, was designed based on known substrates of CYP1B1. Based on the seco-CQ pharmacophore of natural products duocarmycin B2 21 and C2 22, the novel synthesis was achieved via direct allylation of an aniline derivative followed by dihydroxylation to give a 1,2-diol. Selective tosylation of the primary alcohol and protection of the secondary hydroxyl group allowed cyclisation to the 6-membered ring exclusively. Preliminary biological results are also given.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The Design and Synthesis of Duocarmycin Prodrugs
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Duocarmycin; Prodrugs
URI: https://discovery.ucl.ac.uk/id/eprint/10105142
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